Remote hydroxylation of methyl groups by regioselective cyclopalladation. Partial synthesis of hyptatic acid-A

Article abstract of DOI:10.1021/jo070116e

(Chemical Equation Presented) Hyptatic acid-A (32), a 2α,3β,24- trihydroxyolean-12-en-28-oic acid, previously isolated from Hyptis capitata, was obtained from maslinic acid (2). The regioselective cyclopalladation of the axial methyl group on C-4 of maslinic acid afforded the C-24 hydroxymethylene group due to the presence of a C-2-OR substituent. Nevertheless, hederagenin (7) (23-hydroxy derivative) was formed when this oxygenated group was not present.

Full text of DOI:10.1021/jo070116e

Remote Hydroxylation of Methyl Groups by Regioselective
Cyclopalladation. Partial Synthesis of Hyptatic Acid-A
Andre´s Garc´ıa-Granados, Pilar E. Lo´pez, Enrique Melguizo,
Andre´s Parra,* and Yolanda Simeo´
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad de Granada, 18071,
Granada, Spain
aparra@ugr.es
ReceiVed January 19, 2007
Hyptatic acid-A (32), a 2R,3â,24-trihydroxyolean-12-en-28-oic acid, previously isolated from Hyptis
capitata, was obtained from maslinic acid (2). The regioselective cyclopalladation of the axial methyl
group on C-4 of maslinic acid afforded the C-24 hydroxymethylene group due to the presence of a
C-2-OR substituent. Nevertheless, hederagenin (7) (23-hydroxy derivative) was formed when this
oxygenated group was not present.
Introduction
The oxidation of unactivated sp3 C-H bonds is a process
that has found widespread application in synthetic chemistry.1
These oxidative methods have been applied to the functional-
ization of several steroids and terpenoids for synthesizing
different natural products.2 Thus, 2-cyano-3,12-dioxooleana-1,9-
(11)-dien-28-oic acid (CDDO) and related compounds are
potential anti-inflammatory, cancer chemopreventive, and che-
motherapeutic agents. Recently, for the synthesis of a new
important precursor, 23-hydroxy-CDDO-Me was synthesized
from methyl 3,12-dioxooleana-9(11)-en-28-oate by a C-23
oxidation protocol, which involves cyclopalladation of a C-4
methyl group from a 3-one oxime.3
FIGURE 1. Structures of 1-4.
(1) Desai, L.V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 9542-9543 and references therein.
Oximes are among the most useful and versatile synthetic
intermediates in organic chemistry, and they also are of
considerable theoretical interest. For this reason, the preferred
conformation and configuration of oximes has been the subject
of extensive investigation for many years. In this sense, the
(2) (a) Justicia, J.; Oltra, J. E.; Cuerva, J. M. J. Org. Chem. 2005, 70,
8265-8272. (b) Justicia, J.; Oltra, J. E.; Cuerva, J. M. Tetrahedron Lett.
2004, 45, 4293-4296. (c) Johnson, J. A.; Li, N.; Sames, D.; Dangel, B. D.
J. Am. Chem. Soc. 2002, 124, 6900-6903. (d) Godula, K.; Youn, S. W.;
Sezen, B.; Sames, D. J. Am. Chem. 2002, 124, 11856-11857. (e) Bore, L.;
Honda, T.; Gribble, G. W. Nat. Prod. Lett. 2002, 16, 273-276. (g) Bore,
L.; Honda, T.; Gribble, G. W. J. Org. Chem. 2000, 65, 6278-6282. (f)
Peakman, T. M.; ten Haven, H. L.; Rullko¨tter, J. Tetrahedron 1991, 47,
3779-3786. (h) Carr, K.; Saxton, H. M.; Sutherland, J. K. J. Chem. Soc.,
Perkin Trans. 1 1988, 1599-1601. (i) Baldwin, J. E.; Jones, R. H.; Najera,
C.; Yus, M. Tetrahedron 1985, 41, 699-711.
(3) Honda, T.; Janosik, T.; Honda, Y.; Han, J.; Liby, K. T.; Williams,
C. R.; Couch, R. D.; Andeerson, A. C.; Sporn, M. B.; Gribble, G. W.
J. Med. Chem. 2004, 47, 4923-4932.
10.1021/jo070116e CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/03/2007
3500
J. Org. Chem. 2007, 72, 3500-3509

Partial Synthesis of Hyptatic Acid-A
SCHEME 1. Synthesis of the 23-Acetoxy Derivative 8a
a Reagents and conditions: (a) Jones reagent, acetone, rt, 1 h, 98%. (b) NH2OH‚HCl, Py, 50 °C, 45 min, 90%. (c) Na2PdCl4, HOAc, KOAc, rt, 72 h, 90%.
(d) (i) DMAP, Et3N, Ac2O, rt, 45 min; (ii) THF, Py, Pb(OAc)4, HOAc, rt, 24 h; (iii) NaBH4, NaOH (1 N), rt, 10 min, 75% (for three steps). (e) TiCl3,
NH4OAc, H2O, rt, 4 h, 90%.
TABLE 1. 13C NMR Shifts for A-Ring of 3â-Hydroxy-12-Oleanene
Derivatives
Triterpenoids are a large family of natural products biosyn-
thetically derived from squalene and widely found in nature.
24-hydroxy-
Pentacyclic triterpenes and saponins exhibit a wide range of
compound/
carbon
23-hydroxy-
erythrodiol9
methyl
hederagenin
methyl ester9
biological activities, and some of them may be used in medicine.
Erythrodiol and 23-hydroxyerythrodiol (12) are naturally oc-
curring C-28 reduced derivatives of oleanolic acid present in
several plants.8,9 Hederagenin (23-hydroxyoleanolic acid) (13)9,10
has been isolated from various plants and constitutes the
aglycone of several triterpenic saponins.11 Moreover, 24-
hydroxyoleanolic acid was isolated from the roots of Lantana
indica, and its structure was established by chemical and
spectroscopic methods.12 Hyptatic acid-A (2R,3â,24-trihydroxy-
olean-12-en-28-oic acid or 24-hydroxymaslinic acid) (32) has
been isolated as a significant cytotoxic principle of Hyptis
capitata.13 Hyptatic acid-B (2R,3â,19R,24-tetrahydroxyurs-12-
3
10
12
oleanate12
C-1
C-2
C-3
C-4
38.5 38.2 38.4
27.8 27.8 26.9
79.1 77.0 76.9
38.8 41.9 41.9
55.3 49.9 49.8
37.1 37.0 36.9
72.2 72.2
38.3
26.0
75.7
41.7
49.3
36.8
70.3
11.6
38.8
27.6
80.8
41.6
55.9
35.7
22.4
64.4
38.1
26.4
76.4
41.7
49.7
36.9
71.3
11.6
C-5
C-10
C-23
C-24
11.5 11.4
conformationally mobile system of 2-substitued cyclohexanone
oximes has been investigated by means of NMR spectroscopy
and X-ray crystallography.4
(6) (a) Garc´ıa-Granados, A.; Martinez, A.; Parra, A.; Rivas, F. PCT
Int. Appl: W09804331, 1998; Publication Number: EPO894517; http://
v3.espacenet.com/textdoc?DB)EPODOC&IDX)EP0894517&QPN)EP089-
4517; (b) Ibid, Chem Abstr. 1998, 128, 179706.
(7) (a) Garc´ıa-Granados, A.; Lo´pez, P. E.; Melguizo, E.; Moliz, J. N.;
Parra, A.; Simeo´, Y. J. Org. Chem. 2003, 68, 4833-4844. (b) Garc´ıa-
Granados, A.; Lo´pez, P. E.; Melguizo, E.; Parra, A.; Simeo´, Y. Tetrahedron
Lett. 2003, 44, 6673-6677. (c) Garc´ıa-Granados, A.; Lo´pez, P. E.; Melguizo,
E.; Parra, A.; Simeo´, Y. Tetrahedron 2004, 60, 1491-1503. (d) Garc´ıa-
Granados, A.; Lo´pez, P. E.; Melguizo, E.; Parra, A.; Simeo´, Y. Tetrahedron
2004, 60, 3831-3845.
Oleanolic acid (1) and maslinic acid (2) (Figure 1) are
oleanene triterpenic acids5 isolated from the solid wastes of olive
oil pressing. A method to obtain large quantities of both
compounds from these solid residues has been reported by our
group.6 In previous papers, we have described the conversion
of the corresponding esters, 3 and 4, into several A- and C-ring
modified derivatives.7
(4) (a) Saito, H.; Terasawa, I.; Ohno, M.; Nukada, K. J. Am. Chem. Soc.
1969, 91, 6696-6703. (b) Fraser, R. R.; Dhawan, K. L.; Taymaz, K. Org.
Magn. Reson. 1978, 11, 269-274. (c) Ciunik, Z.; Rudolf, K. Pol. J. Chem.
1996, 70, 1030-1035. (d) Ciunik, Z. J. Mol. Struct. 1996, 385, 89-98. (e)
Ribeiro, D. S.; Olivato, P. R.; Rittner, R. Org. Magn. Reson. 2000, 38,
627-638. (f) Olivato, P. R.; Ribeiro, D. S.; Kukerman-Spchpector, J.;
Bombieri, G. Acta Crystallogr., Sect. B 2001, 57, 705-713. (g) Ribeiro,
D. S.; Abraham, R. J. Org. Magn. Reson. 2002, 40, 49-56.
(5) (a) Dictionary of Natural Products on CD-ROM, SIN 0966-2146,
version 5:1; Chapman and Hall: New York, 1996; oleanolic acid CAS (508-
02-01) and maslinic acid CAS [4373-41-5]. (b) Phytochemical and
EthnobotanicalDB;http://www.ars-grin.gov/cgi-bin/duke/chemical.pl?OLEAN-
OLICACID; http://www.ars-grin.gov/cgi-bin/duke/chemical.pl?MASLINI-
CACID.
(8) (a) Monaco, P.; Caputo, R.; Palumbo, G.; Mangoni, L. Phytochemistry
1973, 12, 939-942. (b) Topcu, C.; Ulubelen, A.; Eris, C. Phytochemistry
1994, 36, 743-745. (c) Topcu, C.; Kartal, M.; Ulubelen, A. Phytochemistry
1997, 44, 1393-1395.
(9) Tori, K.; Seo, S.; Shimaoka, A.; Tomita, Y. Tetrahedron Lett. 1974,
48, 4227-4230.
(10) Simonsen, J.; Ross, W. C. J. The Terpenes; Cambridge University:
Cambridge, 1957; Vol. 5, pp 174-208 and references therein.
(11) Mohammad, F. V.; Noorwala, M.; Ahmad, V. U.; Sener, B.
Phytochemistry 1995, 40, 213-218.
(12) Singh, S. K.; Tripathi, V. J.; Singh, R. H. Phytochemistry 1990,
29, 3360-3362.
(13) Yamagishi, T.; Zhang, D. C.; Chang, J. J.; McPhail, D. R.; McPail,
A. T.; Lee, K. H. Phytochemistry 1988, 27, 3213-3216.
J. Org. Chem, Vol. 72, No. 9, 2007 3501

Garc´ıa-Granados et al.
SCHEME 2. Reduction and Demethylation of 23-Hydroxy Derivative 8 and Synthesis of Hederagenin 13a
a Reagents and conditions: (a) i-PrOH, H2O, NaBH4, reflux, 12 h, 9 (35%), 10 (40%), and 11 (20%). (b) THF, LiAlH4, reflux, 1 h, 94%. (c) LiBr, DMF,
reflux, 48 h, 90%.
en-28-oic acid or 24-hydroxytormentic acid) was also isolated
from this plant and, as a glucoside, from Paradrymonia
macrophylla14 and from the Rubus species.15 On the other hand,
arjulonic acid (2R,3â,23-trihydroxyolean-12-en-28-oic acid or
23-hydroxymaslinic acid) was isolated from the trunk wood
extracts of Myrianthus liberecus together with other pentacyclic
triterpenes as their methylesters.16 Many of these naturally
ocurring triterpenoids, together with their structural analogues,
have interesting pharmacological profiles, including in vitro anti-
HIV, antitumoral, and antioxidant properties.17 In fact, via a
pharmacophore search, 2â,3â-dihydroxyolean-12-en-23,28-dioic
acid was identified as being a novel non-peptide HIV-1 protease
inhibitor.18
In light of these results and our research program into the
synthesis of various oleanane triterpenoids to discover new
structures with potential pharmacological activities, we carried
out several remote functionalizations on the gem-dimethyl group
on the C-4 of oleanolic acid and maslinic acid. Here, we describe
the partial synthesis of 23-hydroxyoleanolic acid (hederagenin)
and 24-hydroxymaslinic acid (hyptatic acid-A), two naturally
occurring compounds and other related products, using a
regioselective cyclopalladation. It is the first reported synthesis
of a 24-hydroxy derivative from compounds with a gem-
dimethyl group on C-4 of the triterpenoid skeleton.
Results and Discussion
Our initial aim was the hydroxylation of the hindered C-4
equatorial methyl group of methyl oleanate (3). This function-
alization was achieved according to Baldwin’s method, which
involves cyclopalladation of the methyl group from a 3-oxime
functionality.2 Thus, the oxidation of methyl oleanate yielded
the 3-oxoderivative 519 that was oximated to give methyl
oleanate 3-oxime 6. This oxime was palladated with Na2PdCl4
to give a dimeric organopalladium complex intermediate.
Subsequently, acetylation with Ac2O, oxidation with Pb(OAc)4,
and reductive workup with NaBH4 afforded 7 that was
hydrolyzed with TiCl3 to give a 75% overall yield of product 8
1
(Scheme 1). H- and 13C NMR spectra of 7 and 8 demon-
strated the existence of an AB system belonging to an
acetoxymethylene group (δ 4.11 and 4.06 for product 7 and δ
4.08 and 4.04 for 8) and the loss of the signal of one angular
methyl group on C-4 (C-23 or C-24).
Compound 8 was treated with NaBH4 at reflux in i-PrOH/
H2O to afford 9-11, in which the carbonyl group on C-3 was
reduced fundamentally from the R-face (9 and 10) but also from
the â-face (11) (Scheme 2). Moreover, the reduction of 8 with
LiAlH4 at reflux afforded 23-hydroxyerythrodiol, 12, the
physical and spectral data of which are identical to those given
in the literature9 (Scheme 2). On the other hand, 9 or 10 were
demethylated at C-28 by treatment with LiBr at reflux in DMF
to produce hederagenin 13 (23-hydroxyoleanolic acid).9,10
Compounds 12 and 13 showed a downfield shift of the H-3R
signal (δ 3.63 for 12 and δ 3.67 for 13) with respect to a 24-
hydroxy derivative described in the literature (δ 3.34).12
(14) Terreaux, C.; Maillard, M. P.; Gupta, M. P.; Hostettmann, K.
Phythochemistry 1996, 42, 495-499.
(15) Zhou, X. H.; Kasai, R.; Ohtani, K.; Tanaka, O.; Nie, R. L.; Yang,
C. R.; Zhou, J.; Yamasaki, K. Phythochemistry 1992, 31, 3642-3644.
(16) Tapondjou, A. L.; Ngounou, N. F.; Lontsi, D.; Sondengam, B. L.;
Martin, M. T.; Bodo, B. Phytochemistry 1995, 40, 1761-1764.
(17) (a) Liu, J. Ethnopharmacology 1995, 49, 57-68. (b) Assefa, H.;
Nimrod, A.; Walker, L.; Sindelar, R. Bioorg. Med. Chem. Lett. 2001, 11,
1619-1623. (c) Honda, T. H.; Rounds, B. V.; Bore, L.; Finlay, H. J.;
Favaloro, F. G.; Gribble, G. W.; Suh, N.; Wang, Y.; Sporn, M. B. J. Med.
Chem. 2000, 43, 4233-4246. (d) Kashiwada, Y.; Ikeshiro, Y.; Nagao, T.;
Okabe, H.; Cosentino, L. M.; Lee, K. H. J. Nat. Prod. 2000, 63, 1619-
1622. (e) Montilla, M. P.; Agil, A.; Navarro, C.; Jimenez, M. I.; Garc´ıa-
Granados, A.; Parra, A. Planta Med. 2003, 69, 470-472.
(19) (a) Garc´ıa-Granados, A.; Duen˜as, J.; Moliz, J. N.; Parra, A.; Perez,
F. L.; Dobado, J. A.; Molina, J. J. Chem. Res., Synop. 56-57. (b) Ibid,
J. Chem. Res., Miniprint 2000, 2, 326-339.
(18) Wang, S.; Milne, G. W. A.; Yan, X.; Posey, I. J.; Nicklaus, M. C.;
Graham, L.; Rice, W. G. J. Med. Chem. 1996, 39, 2047-2054.
3502 J. Org. Chem., Vol. 72, No. 9, 2007

Partial Synthesis of Hyptatic Acid-A
SCHEME 3. Synthesis of the 24-Hydroxy Derivatives 22-25a
a Reagents and conditions: (a) Ac2O, Py, rt, 12 h, 14 (30%) and 15 (70%). (b) Benzoyl chloride, rt, 10 min, 16 (20%) and 17 (80%). (c) Jones reagent,
acetone, rt, 1 h, 18 (95%) or 19 (98%). (d) NH2OH‚HCl, Py, 50 °C, 45 min, 20 (75%) or 21 (70%). (e) Na2PdCl4, HOAc, KOAc, rt, 72 h, 90%. (f) (i)
DMAP, Et3N, Ac2O, rt, 45 min; (ii) THF, Py, Pb(OAc)4, HOAc, rt, 24 h; (iii) NaBH4, NaOH (1 N), rt, 10 min, 22 (40%) and 23 (25%) or 24 (35%) and
25 (30%) (for three steps).
This shift can be interpreted as due to the deshielding effect
of a hydroxyl group situated in the C-23 methyl group by the
cyclopalladation process. This C-23 hydroxylation was also
justified by the 13C NMR data of the compound series 7-13.
Table 1 shows the 13C NMR shifts for 10 and 12 (23-
hydroxymethyl oleanate and 23-hydroxyerythrodiol, respec-
tively), and the data are given in the literature for these
compounds9 and the corresponding 24-hydroxy derivative.12
As can be seen from this table, the main difference between
the 23-hydroxy derivative (10 and 12) and the 24-hydroxy
derivative are in C-3, C-5, and C-23 or C-24. Thus, 23-
hydroxyderivatives showed considerable shielding γ-effects for
C-3 (from -2.2 to -3.4 ppm), C-5 (from -5.4 to -6.0 ppm),
and C-24 (around -4.0 ppm) because there were 1,3-diaxial
interactions between the hydrogen atoms on C-23 and on the
C-3 and C-5 γ-carbons.20 These shielding γ-effects are not
present when the new hydroxylation is situated on the C-24
methyl group, and consequently, these carbons resonated at δ
80.8 (C-3), δ 55.9 (C-5), and δ 64.4 (C-24).12 The final
confirmation of assigning the CH2OH group to C-23 was
provided by the NOE difference spectra of 10, which showed
enhancement between the AB quartet signals of 23-CH2OH and
the H-3 and H-5 signals (Figure 2).
We carried out a similar reaction sequence on methyl
maslinate (4) (Scheme 3). In this case, the hydroxyl group at
C-2 was protected as the acetoxy (14 and 15)21 or benzoyloxy
derivatives (16 and 17). Products 15 and 17, which had a free
3â-hydroxyl group, were oxidized, yielding 3-oxo derivatives
1821 and 19, and their oximation processes led to oximes 20
and 21.
Finally, oximes 20 and 21 were palladated by a process
similar to that described previously for 6 to give two 23- or
24-functionalized acetoxy (22 and 23) or benzoyloxy (24 and
25) derivatives (Scheme 3). In fact, these two pairs of
compounds showed the presence of an AB system between δ
(20) Garc´ıa-Granados, A.; Martinez, A.; Onorato, M. E. Magn. Reson.
Chem. 1986, 24, 853-861.
(21) (a) Garc´ıa-Granados, A.; Duen˜as, J.; Melguizo, E.; Moliz, J. N.;
Parra, A.; Perez, F. L.; Dobado, J. A.; Molina, J. J. Chem. Res., Synop.
2000, 212-213. (b) Ibid, J. Chem. Res., Miniprint 2000, 2, 653-670.
J. Org. Chem, Vol. 72, No. 9, 2007 3503

Garc´ıa-Granados et al.
SCHEME 4. Reduction and Demethylation of 24-Hydroxy Derivatives 23-25 and Synthesis of Hyptatic Acid-A 32a
a Reagents and conditions: (a) MeOH, H2O, KOH, rt, 2 h, 26 (80%) from 22, 26 (75%) from 24. (b) TiCl3, NH4OAc, H2O, rt, 4 h, 27 (90%) or 28 (75%).
(c) TiCl3, NH4OAc, H2O, rt, 4 h, (85%). (d) MeOH, H2O, KOH, rt, 2 h, 29 (90%) from 27 and 29 (85%) from 28. (e) i-PrOH, H2O, NaBH4, reflux, 12 h,
80%. (f) THF, LiAlH4, reflux, 1 h, 95%. (g) LiBr, DMF, reflux, 48 h, 90%.
derivatives 27 and 28, which were treated with KOH/MeOH to
obtain the 3-oxo derivative 29. Compound 29 was also obtained
by hydrolysis of oxime 26 (Scheme 4). Reduction of product
29 with NaBH4 at reflux in i-PrOH/H2O afforded 30 in which
the carbonyl group on C-3 was reduced from the R-face.
Furthermore, the reduction of 29 (or products 27 or 28) with
LiAlH4 at reflux afforded the tetrahydroxy derivative 31
(Scheme 4). Finally, the treatment of 30 with LiBr in refluxing
DMF yielded 32. Compounds 30-32 were hydroxymethylene
derivatives that showed an upfield shift of the H-3R signal
(δ 3.14, 3.14, and 3.04, respectively) as compared with the
previously obtained 23-hydroxy derivatives 12 and 13 (δ 3.63
FIGURE 2. Significant NOE correlations for A-ring in 10 and 30.
and 3.67, respectively) and with methyl arjulonate16 (δ 3.39).
These shifts may be due to the loss of the deshielding effect
4.00 and δ 4.50 due to a new acetoxymethylene group on the
that the 23-CH2OH function exerts in 12, 13, and methyl
arjulonate. However, H-3R for several 24-hydroxy derivatives
hyptatic acid-B13 and sericoside14,15 was more shielded and
situated at δ 2.95 and 2.96. Therefore, the cyclopallation process
methyl groups of C-4.
Complete saponification of 22 and 24 with methanolic KOH
afforded trihydroxy derivative 26 (Scheme 4). On the other hand,
hydrolysis of oximes 23 and 25 with TiCl3 gave 3-oxo
3504 J. Org. Chem., Vol. 72, No. 9, 2007

Partial Synthesis of Hyptatic Acid-A
TABLE 2. 13C NMR Shifts for A-Ring for
2r,3â-Dihydroxy-12-Oleanene Derivatives
hyptatic
methyl
carbon
2
30
31
acid-B13a sericoside13,14b arjulonate16
C-1
C-2
C-3
C-4
46.4 46.5 46.6
69.0 69.2 69.2
83.9 85.5 85.5
39.4 43.4 43.4
55.3 56.0 55.9
38.4 39.4 39.4
23.8 23.8
46.1
68.7
85.8
43.7
56.0
39.2
24.2
65.7
47.5
68.6
85.7
43.9
56.6
38.4
24.6
65.6
46.0
68.7
80.1
42.5
48.8
38.2
69.9
12.9
C-5
C-10
C-23
C-24
68.3 69.7
a 24-Hydroxy tormentic acid. b 19-Hydroxy-28-glucosyl hyptatic acid-
A.
FIGURE 3. A-Ring conformation for 6 with no allyloxy substituent
at C-2.
of methyl maslinate had not situated the primary hydroxyl group
at C-23 but at C-24; thus, hyptatic acid-A13 was obtained, and
the hoped-for 23-hydroxy derivative (arjulonic acid)16 was not
formed. In this case, the 13C NMR data of 30 and 31 (Table 2)
showed positive and lower γ-anti effects for C-3 and C-5
because in this 24-hydroxy derivative, the 1,3-diaxial proton
interactions are not possible, and so C-3 and C-5 are more
deshielded (δ 85.5 and δ 56.0, respectively). These values are
comparable to δ 85.8 and 85.7 for the 24-hydroxy derivatives
hyptatic acid-B and sericoside, respectively, and lower than in
the corresponding 23-hydroxy derivative, methyl arjulonate (δ
80.1 for C-3 and δ 48.8 for C-5).16 Finally, the NOE difference
spectra in the A-ring of 30 confirmed this 24-hydroxy func-
tionalization, showing a positive NOE effect between 2â-H, 2H
of the 24-hydroxymethylene group, and 3H of the 25-methyl
group (Figure 2).
A detailed analysis of the NMR spectra of 6 (3-oxime
derivative of methyl oleanate) and 20 or 21 (2-acetoxy- or
2-benzoyloxy-3-oxime derivatives of methyl maslinate) can
justify the different behaviors of these compounds in the
cyclopalladation process. In all cases, the result is a single oxime
in which the O-H and C3-C4 bonds are in an anti disposition.
1
Moreover, in the H NMR spectrum of 6, the protons of C-2
are situated at δ 3.06 (1H, ddd, JH2R-H1â ) 3.3 Hz, JH2R-H1R
)
5.2 Hz, and JH2R-H2â ) 15.4 Hz, H-2R) and δ 2.14 (1H, ddd,
JH2â-H1â ) 5.9 Hz, JH2â-H1R ) 13.9 Hz, and JH2â-H2R ) 15.4
Hz, H-2â). These coupling constants indicate that the A-ring
has a slightly distorted conformation only in the C-3 region
because of the presence on this carbon of one CdN exocyclic
bond.
FIGURE 4. A-Ring conformation for 21 with a benzoyloxy substituent
at C-2.
However, in 21 from methyl maslinate, in which there was
a benzoyloxy group on C-2, H-2â is situated at δ 6.49 (1H, dd,
half-chair conformation in which the electron pair of oxime is
quite near the C-23 methyl group, which can justify its
functionalization in the cyclopalladation process. In addition,
the theoretical coupling constants for this conformation of
JH2â-H1R ) 4.6 Hz and JH2â-H1â ) 8.5 Hz) and H-1â at δ 2.33
(1H, dd, JH1â-H2â ) 8.5 Hz and JH1â-H1R ) 14.4 Hz). From
these coupling constants, we can deduce a severely distorted
conformation from C-1 to C-4 in the A-ring of the structurally
rigid system of the triterpenoid skeleton. In fact, the coupling
constant of 8.5 Hz between H-2â and H-1â indicates that both
protons are almost eclipsed (dihedral angle of 9.26° according
to the Karplus equation), whereas H-2â and H-1R form a
dihedral angle of 132.16° (J ) 4.6 Hz).
product
6 are very similar to the experimental ones
(JH2R-H1â ) 0.5 Hz, JH2â-H1â ) 7.7 Hz, JH2R-H1R ) 8.0 Hz,
and JH2â-H1R ) 10.8 Hz).
Figure 4 shows the most stable conformation for the A-ring
of the C-3 oxime compound when there is a benzoyloxy group
at C-2 (21). This figure confirms that, in this case, the A-ring
has a more distorted conformation in which the benzoyloxy
group is axially oriented on C-2. Also, in this case, the
theoretical coupling constants of H-2 from this conformation
(JH2â-H1R ) 1.2 Hz and JH2â-H1â ) 8.2 Hz) are very similar to
the experimental ones. Consequently, the oxime electron pair
is now nearest to C-24 and can explain its remote palladium-
catalyzed oxygenation.
Moreover, theoretical calculations22 of A-ring conformations
for 6 and 21 are in accordance with the experimental results.
Thus, the most stable conformation for the A-ring of the C-3
oxime compound with no allyloxy substituent (6) is shown in
Figure 3. As can be seen from this figure, the A-ring showed a
(22) Obtained by the MM2 option of the program Chem3D Ultra,
version 8.0 of CambridgeSoft Corporation.
J. Org. Chem, Vol. 72, No. 9, 2007 3505

Garc´ıa-Granados et al.
column to obtain 7 (446 mg, 75%) as a white solid: mp 203-
Conclusion
205 °C; [R]20 +32 (c 1, CHCl3); IR (CHCl3) 2948, 2866, 1734,
D
1719, 1376, 1219 cm-1; 1H NMR (300 MHz, CDCl3): δ 5.29 (1H,
dd, J1 ) J2 ) 3.6 Hz), 4.11 (1H, d, J ) 11.0 Hz), 4.06 (1H, d,
J ) 11.0 Hz), 3.61 (3H, s), 2.83 (2H, m), 2.04 (3H, s), 1.10 (3H,
s), 1.05 (3H, s), 0.97 (3H, s), 0.91 (3H, s), 0.88 (3H, s), 0.75 (3H,
s); 13C NMR (75 MHz, CDCl3): δ 15.0, 16.9, 19.4, 18.0, 19.5,
21.1, 23.6, 23.1, 23.7, 25.8, 27.7, 30.8, 32.0, 32.4, 33.2, 34.0, 37.0,
36.7, 39.4, 41.5, 41.9, 42.9, 45.9, 46.9, 46.9, 48.7, 51.6, 68.4, 122.3,
143.9, 163.0, 171.1, 178.3; HRMS m/z calcd for C33H51NO5Na
564.3660 [M + Na]+, found 564.3664.
Hydrolysis of Methyl 23-Acetoxy-3â-hydroxyiminoolean-12-
en-28-oate (7). To a buffered solution of TiCl3 (0.5 mL of 20%
aqueous HCl solution containing 19% TiCl3) and NH4OAc (200
mg, 2.6 mmol) in water (8 mL) was added a solution of oxime 7
(450 mg, 0.8 mmol) in THF (15 mL). The mixture was stirred at
rt for 4 h and extracted with CH2Cl2. The extract was washed with
saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered,
and evaporated in vacuo to afford a solid that was purified by a
silica gel flash chromatography column to give 8 (394 mg, 90%)
as a colorless oil: [R]20D +68 (c 1, CHCl3); IR (CHCl3) 2933, 2863,
1734, 1459, 1234 cm-1;1H NMR (300 MHz, CDCl3) δ 5.30 (dd,
1H, J1 ) J2 ) 3.6 Hz), 4.08 (d, 1H, J ) 11.1 Hz), 4.04 (d, 1H,
J ) 11.1 Hz), 3.62 (s, 3H), 2.85 (dd, 1H, J1 ) 4.0 Hz, J2 ) 13.9
Hz), 2.42 (m, 2H), 2.01 (s, 3H), 1.13 (s, 3H), 1.04 (s, 3H), 1.00 (s,
3H), 0.92 (s, 3H), 0.89 (s, 3H), 0.78 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 15.0, 17.0, 17.6, 19.6, 20.9, 23.6, 23.2, 23.7, 25.8, 27.8,
30.8, 32.4, 32.1, 33.2, 34.0, 35.0, 37.8, 39.4, 36.5, 41.6, 41.9, 45.9,
46.8, 46.9, 48.5, 50.3, 51.6, 67.7, 122.2, 144.1, 170.8, 178.3, 214.5;
HRMS m/z calcd for C33H50O5Na 549.3553 [M + Na]+, found
549.3556.
In conclusion, the presence or absence of a C-2 oxygenated
substituent determines which methyl group is functionalized,
and the cyclopalladation reaction is a chemically induced
oxygenation of the â-position of the gem-dimethyl group on
C-4 of the terpenoid system. The differing reactivities of methyl
oleanate and methyl maslinate in the cyclopalladation process
is undoubtedly because of steric hindrance by the C-2 oxygen-
ated group in methyl maslinate derivatives. This behavior is
due to different A-ring conformations in methyl oleanate or
methyl maslinate derivatives, in which the electron pair of the
oxime is quite near the C-23 or C-24 methyl group. Therefore,
the presence of a C-2-OR substituent markedly modifies the
A-ring conformation of the triterpenoid compounds with this
group on C-2, explaining their different regioselectivity in the
cyclopalladation process of the methyl groups on C-4.
Experimental Section
Oxidation of Methyl Oleanate (3). Methyl oleanate (3) (794
mg, 1.7 mmol) was dissolved in acetone, and Jones reagent was
added dropwise at room temperature until an orange color persisted.
The excess of reagent was destroyed with MeOH, and the mixture
was diluted with H2O and extracted with CH2Cl2. The organic layer
was neutralized with NaHCO3, dried over anhydrous Na2SO4, and
evaporated to dryness at reduced pressure, and the residue was
chromatographed to obtain 5 (778 mg, 98%).19
Oximation of Methyl 3-Oxooleanate (5). Compound 5 (580
mg, 1.2 mmol) was dissolved in pyridine (7 mL), and NH2OH‚
HCl (172 mg, 2.4 mmol) was added. The reaction mixture was
stirred at 50 °C for 45 min, acidified with 0.1 N HCl solution,
neutralized with saturated aqueous NaHCO3, and extracted with
CH2Cl2. The solvent was evaporated at reduced pressure, and the
residue was chromatographed to afford 6 (542 mg, 90%) as a white
Reduction of Methyl 3-oxo-23-Acetoxyolean-12-en-28-oate (8)
with NaBH4. Compound 8 (200 mg, 0.37 mmol) was dissolved in
i-PrOH/H2O (3:1) (10 mL), and NaBH4 (70 mg, 2 mmol) was
added. The reaction mixture was stirred at reflux for 12 h. The
excess of reagent was destroyed with NaHSO4, and the reaction
mixture was extracted with CH2Cl2. The organic layer was dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The solid residue was purified on a silica gel chromatography
column to give 9 (68 mg, 35%), 10 (72 mg, 40%), and 11 (39 mg,
20%). 9: Colorless oil: [R]20D +70 (c 1, CHCl3); IR (CHCl3) 3439,
2934, 1732, 1458, 1248 cm-1;1H NMR (300 MHz, CDCl3) δ 5.27
(1H, dd, J1 ) J2 ) 3.6 Hz), 4.87 (dd, 1H, J1 ) 4.6 Hz, J2 ) 12.1
Hz), 3.61 (3H, s), 3.36 (1H, d, J ) 12.6 Hz), 2.89 (1H, d, J ) 12.6
Hz), 2.84 (1H, dd, J1 ) 4.4 Hz, J2 ) 13.9 Hz), 2.06 (3H, s), 1.12
(3H, s), 0.95 (3H, s), 0.91 (3H, s), 0.88 (3H, s), 0.71 (3H, s), 0.66
(3H, s); 13C NMR (75 MHz, CDCl3) δ 13.0, 16.0, 16.9, 17.8, 21.2,
23.2, 23.5, 23.7, 26.1, 27.8, 30.8, 30.8, 32.4, 32.5, 33.2, 34.0, 36.8,
38.1, 39.4, 41.4, 41.8, 42.4, 46.0, 46.8, 46.8, 47.6, 51.6, 64.6, 74.8,
122.2, 144.1, 172.4, 178.4; HRMS m/z calcd for C33H52O5Na
551.3712 [M + Na]+, found 551.3716. 10: White solid: mp 229-
solid: mp 235-237 °C; [R]20 +19.4 (c 1, CHCl3); IR (CHCl3)
D
3319, 2947, 1725, 1461, 1165 cm-1; 1H NMR (300 MHz, CDCl3)
δ 5.28 (1H, dd, J1 ) J2 ) 3.5 Hz), 3.61 (3H, s), 3.06 (1H, ddd,
J1 ) 3.3 Hz, J2 ) 5.2 Hz, J3 ) 15.4 Hz), 2.85 (1H, dd, J1 ) 4.3
Hz, J2 ) 13.8 Hz), 2.14 (1H, ddd, J1 ) 5.9 Hz, J2 ) 13.9 Hz, J3
) 15.4 Hz), 1.14 (3H, s), 1.10 (3H, s), 1.04 (3H, s), 1.01 (3H, s),
0.91 (3H, s), 0.88 (3H, s), 0.75 (3H, s); 13C NMR (75 MHz, CDCl3)
δ 15.0, 16.9, 17.1, 19.1, 23.1, 23.3, 23.6, 23.7, 25.9, 27.2, 27.7,
30.8, 32.4, 32.5, 33.2, 33.9, 37.2, 38.5, 39.4, 40.4, 41.4, 41.8, 45.9,
46.8, 47.3, 51.6, 55.9, 122.3, 143.9, 167.1, 178.3; HRMS m/z calcd
for C31H49NO3Na 506.3618 [M + Na]+, found 506.3620.
Cyclopalladation of Methyl 3-Hydroxyiminoolean-12-en-28-
oate (6). To a solution of methyl 3-hydroxyiminoolean-12-en-28-
oate (6) (524 mg, 1.1 mmol) in HOAc (50 mL), KOAc (128 mg,
1.3 mmol) and Na2PdCl4 (383 mg, 1.3 mmol) were added. The
solution was stirred for 72 h at room temperature (rt), and cooled
water (100 mL) was added to give a yellow precipitate. The
palladium complex was filtered through Celite and dried in vacuo
at rt for 24 h. To a solution of this yellow solid in dry CH2Cl2 (50
mL) were added DMAP (4 mg), Et3N (0.25 mL), and Ac2O (0.15
mL). The mixture reaction was stirred at rt for 45 min, washed
with water, dried over anhydrous Na2SO4, filtered, and evaporated
at reduced pressure. The crude product was dissolved again in dry
THF (40 mL), and pyridine (0.1 mL) was added. The reaction
mixture was stirred for 15 min at room temperature and cooled at
- 80 °C, and a solution of Pb(OAc)4 (536 mg, 1.2 mmol) in HOAc
(10 mL) was added and again stirred at rt for 24 h. To remove the
remaining Pd salts, a solution of NaBH4 (40 mg) in 1 N NaOH
solution (30 mL) was added to the reaction mixture. The mixture
was stirred for 10 min and filtered. The filtrate was diluted with
CH2Cl2 (75 mL), which was washed with saturated aqueous
NaHCO3 solution, dried over Na2SO4, filtered, and evaporated in
vacuo to give a solid. The crude product was purified on a silica
230 °C; [R]20 +68 (c 1, CHCl3); IR (CHCl3) 3364, 2930, 2857,
D
1725, 1459 cm-1;1H NMR (300 MHz, CDCl3) δ 5.26 (1H, dd,
J1 ) J2 ) 3.6 Hz), 3.71 (1H, d, J ) 10.4 Hz), 3.63 (1H, dd, J1 )
4.8 Hz, J2 ) 10.1 Hz), 3.61 (3H, s), 3.41 (d, 1H, J ) 10.4 Hz),
2.84 (1H, dd, J1 ) 4.2 Hz, J2 ) 13.7 Hz), 1.24 (3H, s), 1.11 (3H,
s), 0.94 (3H, s), 0.91 (3H, s), 0.88 (3H, s), 0.71 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 11.5, 15.8, 17.0, 18.6, 23.5, 23.2, 23.7, 26.1,
26.9, 27.8, 30.8, 32.5, 32.6, 33.2, 34.0, 37.0, 38.2, 39.4, 41.4, 41.8,
41.9, 46.0, 46.8, 47.7, 49.9, 51.6, 72.2, 77.0, 122.4, 143.9, 178.4;
HRMS m/z calcd for C31H50O4Na 509.3607 [M + Na]+, found
509.3607. 11: Colorless oil: [R]20D +51 (c 1, CHCl3); IR (CHCl3)
3444, 2933, 2863, 1726, 1251 cm-1;1H NMR (300 MHz, CDCl3)
δ 5.27 (1H, dd, J1 ) J2 ) 3.6 Hz), 4.18 (1H, d, J ) 11.5 Hz), 3.81
(1H, d, J ) 11.5 Hz), 3.61 (3H, s), 3.41 (dd, 1H, J1 ) 4.8 Hz,
J2 ) 4.8 Hz), 2.85 (1H, dd, J1 ) 4.4 Hz, J2 ) 14.3 Hz), 2.09 (3H,
s), 1.11 (3H, s), 0.93 (3H, s), 0.91 (3H, s), 0.89 (3H, s), 0.77 (3H,
s), 0.71 (3H, s); 13C NMR (75 MHz, CDCl3) δ 12.9, 15.9, 17.0,
18.3, 21.1, 23.2, 23.5, 23.7, 26.0, 26.2, 27.8, 30.8, 32.4, 32.5, 33.2,
3506 J. Org. Chem., Vol. 72, No. 9, 2007

Partial Synthesis of Hyptatic Acid-A
34.0, 37.0, 38.3, 39.4, 41.4, 41.7, 42.1, 46.0, 46.8, 47.9, 48.4, 51.6,
67.6, 72.8, 122.4, 143.9, 171.5, 178.3; HRMS m/z calcd for
C33H52O5Na 551.3712 [M + Na]+, found 551.3712.
3.37 (1H, d, J ) 10.0 Hz), 2.84 (1H, dd, J1 ) 4.3 Hz, J2 ) 13.8
Hz), 2.11 (1H, dd, J1 ) 4.4 Hz, J2 ) 12.1 Hz), 1.12 (3H, s), 1.08
(3H, s), 1.08 (3H, s), 0.91 (3H, s), 0.90 (3H, s), 0.88 (3H, s), 0.72
(3H, s); 13C NMR (75 MHz, CDCl3) δ 16.5, 16.8, 16.9, 18.4, 23.1,
23.6, 23.7, 26.0, 27.7, 28.7, 30.8, 32.4, 32.6, 33.2, 33.9, 38.5, 39.4,
40.0, 41.3, 41.8, 43.8, 45.9, 46.8, 47.7, 51.6, 55.3, 74.1, 81.0, 122.1,
128.4, 128.4, 129.7, 129.7, 130.5, 133.1, 143.9, 167.1, 178.3; HRM
m/z calcd for C38H54O5Na 613.3870 [M + Na]+, found 613.3870.
Oxidation of Methyl 2R-Acetoxy-3â-hydroxy-12-en-28-oate
(15). Compound 15 (1500 mg, 2.5 mmol) was dissolved in acetone,
and Jones reagent was added dropwise at room temperature until
an orange color persisted. The excess of reagent was destroyed with
MeOH, and the mixture was diluted with H2O and extracted with
CH2Cl2. The organic layer was neutralized with NaHCO3, dried
over anhydrous Na2SO4, and evaporated to dryness at reduced
pressure, and the residue was chromatographed to obtain 18 (1250
mg, 95%).21
Reduction of Methyl 23-Acetoxy-3-oxoolean-12-en-28-oate (8)
with LiAlH4. Compound 8 (200 mg, 0.38 mmol) was dissolved in
dry THF (10 mL), and a solution of 1 M LiAlH4 in THF (1 mL)
was added. The reaction mixture was stirred for 1 h at reflux, the
excess of the reagent was destroyed with MeOH, and the solvent
was concentrated under reduced pressure. The crude product was
purified on a silica column to give (12)9 (164 mg, 94%). IR (CHCl3)
1
3344, 2930, 2857, 1725, 1459, 756 cm-1; H NMR (300 MHz,
CDCl3) δ 5.18 (1H, dd, J1 ) J2 ) 3.6 Hz), 3.72 (1H, d, J ) 10.3
Hz), 3.63 (dd, 1H, J1 ) 6.8 Hz, J2 ) 9.0 Hz), 3.53 (1H, d, J )
11.0 Hz), 3.42 (1H, d, J ) 10.3 Hz), 3.20 (1H, d, J ) 11.0 Hz),
1.15 (3H, s), 0.97 (3H, s), 0.93 (3H, s), 0.89 (3H, s), 0.87 (3H, s),
0.86 (3H, s); 13C NMR (75 MHz, CDCl3) δ 11.4, 16.0, 16.8, 18.6,
22.1, 23.6, 23.7, 25.6, 26.0, 26.9, 31.0, 31.1, 32.5, 33.3, 34.2, 36.9,
37.0, 38.4, 39.9, 41.9, 42.0, 42.4, 46.6, 47.6, 49.8, 69.7, 72.2, 76.9,
122.4, 143.9; HRMS m/z calcd for C30H50O3Na 481. 3714 [M +
Na]+, found 481.3720.
Oxidation of Methyl 2R-Benzoyloxy-3â-hydroxyolean-12-en-
28-oate (17). Compound 17 (1200 mg, 2 mmol) was dissolved in
acetone, and Jones reagent was added dropwise at room temperature
until an orange color persisted. The excess of reagent was destroyed
with MeOH, and the mixture was diluted with H2O and extracted
with CH2Cl2. The organic layer was neutralized with NaHCO3, dried
over anhydrous Na2SO4, and evaporated to dryness at reduced
pressure, and the residue was chromatographed to obtain 19 (1175
Demethylation at C-28 of 23-Hydroxy Derivatives 9 and 10.
Compound 9 was dissolved in DMF (3 mL), and LiBr (10 eq) was
added. The reaction mixture was stirred at reflux for 48 h, and
DMF was removed at reduced pressure. The crude product was
purified on a silica column to afford (13)9,10 (157 mg, 90%). IR
(CHCl3) 3335, 2928, 2850, 1692, 1457 cm-1; 1H NMR (300 MHz,
CDCl3) δ 5.31 (1H, dd, J1 ) J2 ) 3.6 Hz), 3.67 (1H, dd, J1 ) 5.0
Hz, J2 ) 10.8 Hz), 3.59 (d, 1H, J ) 10.9 Hz), 3.36 (d, 1H, J )
10.9 Hz), 2.92 (1H, dd, J1 ) 4.2 Hz, J2 ) 13.4 Hz), 1.24 (3H, s),
1.04 (3H, s), 1.01 (3H, s), 0.98 (3H, s), 0.89 (3H, s), 0.77 (3H, s);
13C NMR (75 MHz, CDCl3) δ 12.7, 16.3, 17.8, 19.2, 24.0, 24.1,
24.5, 26.4, 27.4, 28.9, 31.6, 33.5, 33.5, 33.8, 34.9, 37.9, 38.5, 40.5,
42.8, 43.0, 43.3, 47.3, 47.7, 48.8, 49.9, 67.6, 74.1, 123.6, 145.3,
181.8; HRMS m/z calcd for C30H48O4Na 495.3450 [M + Na]+,
found 495.3451. A similar procedure was followed for 10.
Acetylation of Methyl Maslinate 4. Methyl maslinate (4) (1.2
g, 2.5 mmol) was dissolved in pyridine (5 mL), and Ac2O (1.2
mL, 10 mmol) was added, stirring the reaction for 12 h at rt. The
reaction was diluted with cooled water and extracted with CH2Cl2.
The organic layer was acidified with aq HCl solution (20 mL, 10%),
neutralized with NaHCO3 solution (50 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified on a silica column to give 14 (427 mg, 30%) and 15
(924 mg, 70%).21
mg, 98%) as colorless oil: [R]20 +30 (c 1, CHCl3); IR (CHCl3)
D
2946, 1721, 1460, 1272, 1119, 756, 711 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.4-8.1 (5H, m), 5.85 (1H, dd, J1 ) 6.1 Hz, J2 ) 13.3
Hz), 5.29 (1H, dd, J1 ) J2 ) 3.5 Hz), 3.63 (3H, s), 2.87 (1H, dd,
J1 ) 4.2 Hz, J2 ) 13.8 Hz), 2.35 (1H, dd, J1 ) 6.1 Hz, J2 ) 12.3
Hz), 1.34 (3H, s), 1.20 (3H, s), 1.14 (3H, s), 1.12 (3H, s), 0.92
(3H, s), 0.89 (3H, s), 0.79 (3H, s); 13C NMR (75 MHz, CDCl3) δ
16.0, 17.1, 19.2, 21.4, 23.1, 23.7, 23.7, 25.0, 26.0, 27.8, 30.8, 32.4,
32.4, 33.2, 33.9, 38.1, 39.5, 41.3, 41.8, 45.8, 45.9, 46.8, 47.5, 48.9,
51.6, 57.3, 72.3, 121.8, 128.4, 128.4, 129.9, 129.9, 130.0, 133.1,
144.2, 165.9, 178.3, 209.0; HRMS m/z calcd for C38H52O5Na
611.3712 [M + Na]+, found 611.3714.
Oximation of Methyl 3-oxo-2R-Acetoxyolean-12-en-28-oate
(18). Compound 18 (2000 mg, 3.8 mmol) was dissolved in pyridine
(20 mL), and NH2OH‚HCl (530 mg, 7.6 mmol) was added. The
reaction mixture was stirred at 50 °C for 1 h, acidified with 0.1 N
HCl solution, neutralized with saturated aqueous NaHCO3, and
extracted with CH2Cl2. The solvent was evaporated at reduced
pressure, and the residue was chromatographed to afford 20 (1540
mg, 75%) as a white solid: mp 194-196 °C; [R]20 +49 (c 1,
Benzoylation of Methyl Maslinate 4. Methyl maslinate (4) (1.2
g, 2.5 mmol) was dissolved in pyridine (5 mL), and benzoyl chloride
(1.2 mL, 10 mmol) was added. The reaction was stirred for 10
min at rt. The reaction was diluted with cooled water and extracted
with CH2Cl2. The organic layer was acidified with aq HCl solution
(20 mL, 10%), neutralized with NaHCO3 solution (50 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified on a silica column to afford 16
D
CHCl3); IR (CHCl3): 3433, 2948, 1729, 1237, 756 cm-1; 1H NMR
(300 MHz, CDCl3) δ 6.20 (1H, dd, J1 ) 5.2 Hz, J2 ) 8.7 Hz),
5.29 (1H, dd, J1 ) J2 ) 3.5 Hz), 3.60 (3H, s), 2.85 (1H, dd, J1 )
4.3 Hz, J2 ) 14.0 Hz), 2.24 (1H, dd, J1 ) 8.7 Hz, J2 ) 14.2 Hz),
2.03 (3H, s), 1.24 (3H, s), 1.15 (3H, s), 1.13 (3H, s), 0.91 (3H, s),
0.88 (3H, s), 0.83 (3H, s), 0.73 (3H, s); 13C NMR (75 MHz, CDCl3)
δ 16.2, 16.5, 19.9, 21.2, 23.2, 23.6, 23.7, 23.8, 25.8, 27.7, 30.8,
32.0, 32.4, 32.5, 33.2, 34.0, 36.8, 39.2, 39.4, 41.6, 42.0, 45.1, 45.9,
46.4, 46.9, 51.6, 52.4, 62.2, 122.4, 143.6, 162.4, 170.0, 178.3;
HRMS m/z calcd for C33H51NO5 542.3840 [M + H]+, found
542.383.
(348 mg, 20%) and 17 (1160 mg, 80%). 16: Colorless oil: [R]20
D
-12 (c 1, CHCl3); IR (CHCl3) 2946, 1723, 1279, 710 cm-1;1H
NMR (300 MHz, CDCl3) δ 7.4-8.2 (10H, m), 5.46 (1H, ddd,
J1 ) 4.6 Hz, J2 ) J3 ) 10.4 Hz), 5.26 (1H, dd, J1 ) J2 ) 3.4 Hz),
5.21 (1H, d, J ) 10.4 Hz), 3.62 (3H, s), 2.86 (1H, dd, J1 ) 4.0 Hz,
J2 ) 13.9 Hz), 2.25 (1H, dd, J1 ) 4.6 Hz, J2 ) 12.3 Hz), 1.17
(3H, s), 1.14 (3H, s), 1.09 (3H, s), 1.00 (3H, s), 0.91 (3H, s), 0.89
(3H, s), 0.75 (3H, s); 13C NMR (75 MHz, CDCl3) δ 16.6, 16.9,
17.9, 18.4, 23.1, 23.6, 23.7, 26.0, 27.7, 28.6, 30.8, 32.4, 32.6, 33.2,
34.0, 38.5, 39.5, 39.9, 41.3, 41.8, 44.0, 45.9, 46.8, 47.7, 51.6, 55.2,
71.1, 81.1, 122.1, 128.3, 128.3, 128.9, 129.6, 129.6, 130.2, 130.3,
130.6, 132.8, 132.9, 134.6, 162.4, 143.9, 166.3, 166.5, 178.3; HRMS
m/z calcd for C45H58O6Na 717.4131 [M + Na]+, found 717.4132.
Oximation of Methyl 3-oxo-2R-Benzoyloxyolean-12-en-28-
oate (19). Compound 19 (2400 mg, 4.1 mmol) was dissolved in
pyridine (22 mL), and NH2OH‚HCl (572 mg, 8.2 mmol) was added.
The reaction mixture was stirred at 50 °C for 1 h, acidified with
0.1 N HCl solution, neutralized with saturated aqueous NaHCO3,
and extracted with CH2Cl2. The solvent was evaporated at reduced
pressure, and the residue was chromatographed to afford 21 (1.72
g, 70%) as a colorless oil: [R]20 +42 (c 1, CHCl3); IR (CHCl3)
D
3436, 2949, 1722, 1270, 756, 712 cm-1
;
1H NMR (300 MHz,
17: White solid: mp 125-127 °C; [R]20 +12 (c 1, CHCl3); IR
CDCl3) δ 7.4-8.0 (5H, m), 6.49 (1H, dd, J1 ) 4.6 Hz, J2 ) 8.5
Hz), 5.29 (1H, dd, J1 ) J2 ) 3.5 Hz), 3.61 (3H, s), 2.85 (1H, dd,
J1 ) 4.0 Hz, J2 ) 13.6 Hz), 2.33 (1H, dd, J1 ) 8.5 Hz, J2 ) 14.4
Hz), 1.30 (3H, s), 1.18 (3H, s), 1.12 (3H, s), 0.90 (3H, s), 0.89
D
1
(CHCl3) 3463, 2947, 1720, 1277, 756 cm-1; H NMR (300 MHz,
CDCl3) δ 7.4-8.1 (5H, m), 5.25 (1H, dd, J1 ) J2 ) 3.5 Hz), 5.19
(1H, ddd, J1 ) 4.4 Hz, J2 ) 10.0 Hz, J3 ) 11.3 Hz), 3.61 (3H, s),
J. Org. Chem, Vol. 72, No. 9, 2007 3507

Garc´ıa-Granados et al.
(3H, s), 0.87 (3H, s), 0.75 (3H, s); 13C NMR (75 MHz, CDCl3) δ
16.5, 16.5, 20.0, 23.0, 23.2, 23.6, 23.6, 25.7, 27.7, 30.7, 32.1, 32.4,
32.5, 33.1, 34.0, 36.8, 39.2, 39.4, 41.6, 42.0, 45.3, 45.8, 46.5, 46.9,
51.6, 52.4, 62.7, 122.4, 128.4, 128.4, 129.7, 129.7, 130.4, 133.0,
143.6, 162.3, 165.6, 178.3; HRMS m/z calcd for C38H53NO5Na
626.3821 [M + Na]+, found 626.3818.
remaining Pd salts, a solution of NaBH4 (140 mg) in 1 N NaOH
solution (45 mL) was added to the reaction mixture. It was stirred
for 10 min and filtered. The filtrate was diluted with CH2Cl2 (250
mL), which was washed with saturated aqueous NaHCO3 solution,
dried over Na2SO4, filtered, and evaporated in vacuo to give a solid.
The crude product was purified on a silica column to afford 24
(738 mg, 35%) and 25 (595 mg, 30%). 24: Colorless oil: [R]20
Cyclopalladation of Methyl 2R-Acetoxy-3-hydroxyiminoolean-
12-en-28-oate (20). To a solution of 2R-acetoxy-3-hydroxyimi-
noolean-12-en-28-oate (20) (1400 mg, 2.5 mmol) in HOAc (160
mL), KOAc (270 mg, 2.8 mmol) and Na2PdCl4 (830 mg, 2.8 mmol)
were added. The solution was stirred for 72 h at rt, and cooled
water (250 mL) was added to give a yellow precipitate. The
palladium complex was filtered through Celite and dried in vacuo
at rt for 24 h. To a solution of this yellow solid in dry CH2Cl2 (120
mL) were added DMAP (6 mg), Et3N (0.5 mL), and Ac2O (0.4
mL). The reaction mixture was stirred at rt for 45 min, washed
with water, dried over anhydrous Na2SO4, filtered, and evaporated
at reduced pressure. The crude product was dissolved again in dry
THF (100 mL), and pyridine (0.2 mL) was added. The reaction
mixture was stirred for 15 min at room temperature and cooled at
- 80 °C, and a solution of Pb(OAc)4 (1160 mg, 2.6 mmol) in HOAc
(40 mL) was added and again stirred at rt for 24 h. To remove the
remaining Pd salts, a solution of NaBH4 (105 mg) in 1 N NaOH
solution (38 mL) was added to the reaction mixture. The mixture
was stirred for 10 min and filtered. The filtrate was diluted with
CH2Cl2 (200 mL), which was washed with saturated aqueous
NaHCO3 solution, dried over Na2SO4, filtered, and evaporated in
vacuo to give a solid. The crude product was purified on a silica
column to obtain 22 (641 mg, 40%) and 23 (387 mg, 25%). 22:
D
+16 (c 1, CHCl3); IR (CHCl3) 2947, 1725, 1452, 1370, 1267, 1241,
1
756, 712 cm-1; H NMR (300 MHz, CDCl3) δ 7.4-8.0 (5H, m),
6.21 (1H, dd, J1 ) J2 ) 8.4 Hz), 5.29 (1H, dd, J1 ) J2 ) 3.4 Hz),
4.46 (1H, d, J ) 11.6 Hz), 4.33 (1H, d, J ) 11.6 Hz), 3.61 (3H, s),
2.86 (1H, dd, J1 ) 4.0 Hz, J2 ) 13.6 Hz), 2.45 (1H, dd, J1 ) 8.4
Hz, J2 ) 13.3 Hz), 2.03 (3H, s), 1.91 (3H, s), 1.44 (3H, s), 1.11
(3H, s), 0.98 (3H, s), 0.91 (3H, s), 0.87 (3H, s), 0.76 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 15.8, 16.8, 19.4, 19.6, 21.1, 23.1, 23.6,
24.0, 25.8, 27.7, 28.3, 30.8, 32.4, 32.4, 33.2, 33.9, 36.7, 39.2, 41.5,
41.9, 43.9, 45.8, 44.1, 45.7, 46.8, 51.6, 55.6, 64.4, 66.5, 122.1,
128.6, 128.6, 129.7, 129.7, 129.7, 133.4, 143.9, 165.2, 166.5, 167.7,
170.7, 178.2; HRMS m/z calcd for C42H57NO8Na 726.3982 [M +
Na]+, found 726.3984. 25: Colorless oil: [R]D +35 (c 1, CHCl3);
IR (CHCl3) 3417, 2948, 1722, 1267, 755 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.4-8.0 (5H, m), 6.38 (1H, dd, J1 ) 7.1 Hz, J2 ) 8.5
Hz), 5.27 (1H, dd, J1 ) J2 ) 3.1 Hz), 4.43 (1H, d, J ) 11.5 Hz),
4.12 (1H, d, J ) 11.5 Hz), 3.59 (3H, s), 2.83 (1H, dd, J1 ) 3.9 Hz,
J2 ) 13.7 Hz), 2.46 (1H, dd, J1 ) 8.5 Hz, J2 ) 13.8 Hz), 1.95
(3H, s), 1.31 (3H, s), 1.08 (3H, s), 0.89 (3H, s), 0.88 (3H, s), 0.85
(3H, s), 0.72 (3H, s); 13C NMR (75 MHz, CDCl3) δ 16.0, 16.6,
19.5, 21.0, 23.1, 23.6, 23.9, 25.7, 27.6, 28.2, 30.7, 32.3, 32.3, 33.1,
33.9, 36.4, 39.1, 41.4, 41.9, 42.3, 44.1, 45.7, 45.7, 46.8, 51.6, 54.7,
62.6, 66.9, 122.3, 128.4, 128.4, 129.7, 129.7, 130.2, 133.0, 143.6,
158.5, 165.5, 171.1, 178.3; HRMS m/z calcd for C40H55NO7Na
684.3872 [M + Na]+, found 684.3876.
Colorless oil: [R]20 +55 (c 1, CHCl3); IR (CHCl3) 2947, 1776,
D
1
1743, 1233, 755 cm-1; H NMR (300 MHz, CDCl3) δ 5.96 (1H,
dd, J1 ) J2 ) 8.4 Hz), 5.27 (1H, dd, J1 ) J2 ) 3.4 Hz), 4.42 (1H,
d, J ) 11.6 Hz), 4.23 (1H, d, J ) 11.6 Hz), 3.59 (3H, s), 2.84 (1H,
dd, J1 ) 4.0 Hz, J2 ) 13.6 Hz), 2.30 (1H, dd, J1 ) 8.6 Hz, J2 )
13.4 Hz), 2.09 (3H, s), 2.03 (3H, s), 1.99 (3H, s), 1.32 (3H, s),
1.10 (3H, s), 0.90 (3H, s), 0.89 (3H, s), 0.87 (3H, s), 0.72 (3H, s);
13C NMR (75 MHz, CDCl3) δ 15.8, 16.7, 19.4, 19.6, 20.9, 21.1,
23.1, 23.6, 24.0, 25.8, 27.6, 28.3, 30.8, 32.3, 32.4, 33.2, 33.9, 36.6,
39.1, 41.5, 41.9, 43.7, 43.8, 45.5, 45.8, 46.8, 51.6, 55.4, 63.6, 66.4,
122.1, 143.9, 166.4, 168.1, 169.4, 170.6, 178.2; HRMS m/z calcd
for C37H55NO8Na 664.3832 [M + Na]+, found 664.3825. 23:
Saponification of Methyl 2R,24-Diacetoxy-3-acetoxyiminoolean-
12-en-28-oate (22). Triacetoxy oxime 22 (300 mg, 0.47 mmol) was
dissolved in MeOH (5 mL), and MeOH/H2O (70%) (5 mL)
containing KOH (20%) was added. The reaction mixture was stirred
at rt for 2 h, neutralized with (20%) HCl solution, and extracted
with CH2Cl2. The extract was washed with saturated NaHCO3
solution, dried over anhydrous Na2SO4, and evaporated in vacuo.
Chromatography on a silica gel column yielded 26 (192 mg, 80%)
as a colorless oil: [R]20D +34 (c 1, CHCl3); IR (CHCl3) 3367, 2930,
1726, 1460, 1261, 1035, 757 cm-1; 1H NMR (300 MHz, CDCl3) δ
5.31 (1H, dd, J1 ) J2 ) 3.3 Hz), 4.90 (1H, dd, J1 ) J2 ) 9.2 Hz),
3.79 (1H, d, J ) 10.9 Hz), 3.61 (3H, s), 3.51 (1H, d, J ) 10.9 Hz),
2.86 (1H, dd, J1 ) 4.0 Hz, J2 ) 13.5 Hz), 1.37 (3H, s), 1.12 (3H,
s), 0.91 (3H, s), 0.89 (3H, s), 0.82 (3H, s), 0.73 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 15.6, 16.8, 19.2, 23.2, 23.7, 23.9, 25.7, 27.4,
27.7, 30.8, 32.5, 32.5, 33.2, 34.0, 36.7, 39.1, 41.5, 42.0, 43.6, 44.1,
45.1, 45.8, 46.9, 51.6, 54.8, 62.5, 67.2, 122.4, 143.8, 168.5, 178.3;
HRMS m/z calcd for C31H49NO5 Na 538.3508 [M + Na]+, found
538.3498.
Saponification of Methyl 2R-Benzoyloxy-24-acetoxy-3-acet-
oxyiminoolean-12-en-28-oate (24). Benzoyloxydiacetoxyoxime 24
(300 mg, 0.43 mmol) was dissolved in MeOH (5 mL), and MeOH/
H2O (70%) (5 mL) containing KOH (20%) was added. The reaction
mixture was stirred at rt for 2 h, neutralized with (20%) HCl
solution, and extracted with CH2Cl2. The extract was washed with
saturated NaHCO3 solution, dried over anhydrous Na2SO4, and
evaporated in vacuo. Chromatography on a silica gel column yielded
26 (165 mg, 75%).
syrup: [R]20 +48 (c 1, CHCl3); IR (CHCl3) 2947, 1775, 1743,
D
1
1234, 756 cm-1; H NMR (300 MHz, CDCl3) δ 6.16 (1H, dd,
J1 ) J2 ) 8.4 Hz), 5.25 (1H, dd, J1 ) J2 ) 3.4 Hz), 4.42 (1H, d,
J ) 11.5 Hz), 4.03 (1H, d, J ) 11.5 Hz), 3.58 (3H, s), 2.84 (1H,
dd, J1 ) 4.0 Hz, J2 ) 13.6 Hz), 2.29 (1H, dd, J1 ) 8.5 Hz, J2 )
13.4 Hz), 2.03 (3H, s), 1.99 (3H, s), 1.20 (3H, s), 1.08 (3H, s),
0.89 (3H, s), 0.88 (3H, s), 0.86 (3H, s), 0.70 (3H, s); 13C NMR (75
MHz, CDCl3) δ 15.8, 16.7, 19.3, 19.5, 21.1, 23.0, 23.6, 24.0, 25.7,
27.7, 28.4, 30.8, 32.3, 32.4, 33.3, 34.0, 36.7, 39.0, 41.5, 41.9, 42.5,
43.5, 45.5, 45.8, 46.8, 51.6, 54.6, 62.2, 66.7, 122.1, 143.9, 166.4,
169.4, 170.3, 178.2; HRMS m/z calcd for C35H53NO7Na 622.3366
[M + Na]+, found 623.3372.
Cyclopalladation of Methyl 2R-Benzoyloxy-3-hydroxyimi-
noolean-12-en-28-oate (21). To a solution of 2R-benzoyloxy-3-
hydroxyiminoolean-12-en-28-oate (21) (1800 mg, 3.4 mmol) in
HOAc (180 mL), KOAc (324 mg, 3.3 mmol) and Na2PdCl4 (1000
mg, 3.4 mmol) were added. The solution was stirred for 72 h at rt,
and cooled water (260 mL) was added to give a yellow precipitate.
The palladium complex was filtered through Celite and dried in
vacuo at rt for 24 h. To a solution of this yellow solid in dry CH2-
Cl2 (150 mL) were added DMAP (8 mg), Et3N (0.7 mL), and Ac2O
(0.5 mL). The mixture reaction was stirred at rt for 45 min, washed
with water, dried over anhydrous Na2SO4, filtered, and evaporated
at reduced pressure. The crude product was dissolved again in dry
THF (130 mL), and pyridine (0.25 mL) was added. The reaction
mixture was stirred for 15 min at room temperature and cooled at
- 80 °C, and a solution of Pb(OAc)4 (1250 mg, 2.8 mmol) in HOAc
(52 mL) was added and again stirred at rt for 24 h. To remove the
Hydrolysis of Methyl 2R,24-Diacetoxy-3-hydroxyiminoolean-
12-en-28-oate (23). To a buffered solution of TiCl3 (0.15 mL of
20% aqueous HCl solution containing 19% TiCl3) and NH4OAc
(70 mg, 0.9 mmol) in water (3 mL) was added a solution of oxime
23 (150 mg, 0.23 mmol) in THF (5 mL). The mixture was stirred
at rt for 4 h and extracted with CH2Cl2. The extract was washed
with saturated aqueous NaHCO3 solution, dried over Na2SO4,
filtered, and evaporated in vacuo to afford a solid that was purified
by silica gel flash chromatography column to give 27 (124 mg,
3508 J. Org. Chem., Vol. 72, No. 9, 2007

Partial Synthesis of Hyptatic Acid-A
90%) as a colorless oil: [R]20D +62 (c 1, CHCl3); IR (CHCl3) 2947,
1239, 1743, 756 cm-1;1H NMR (300 MHz, CDCl3) δ 5.54 (1H,
dd, J1 ) 6.0 Hz, J2 ) 13.2 Hz), 5.26 (1H, dd, J1 ) J2 ) 3.6 Hz),
4.74 (1H, d, J ) 11.5 Hz), 3.93 (1H, d, J ) 11.5 Hz), 3.63 (3H, s),
2.85 (1H, dd, J1 ) 4.3 Hz, J2 ) 13.8 Hz), 2.22 (1H, dd, J1 ) 6.1
Hz, J2 ) 12.4 Hz), 2.11 (3H, s), 2.00 (3H, s), 1.32 (3H, s), 1.21
(3H, s), 1.08 (3H, s), 0.90 (3H, s), 0.88 (3H, s), 0.74 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 16.8, 16.9, 19.7, 20.1, 20.7, 20.8, 23.0,
23.7, 23.8, 25.9, 27.7, 30.8, 32.3, 32.7, 33.1, 33.9, 37.9, 39.4, 41.2,
41.7, 45.9, 46.1, 46.6, 47.7, 51.7, 53.8, 58.3, 66.1, 72.2, 122.5,
144.2, 169.9, 171.1, 178.2, 206.4; HRMS m/z calcd for C35H52O7-
Na 607.3606 [M + Na]+, found 607.3610.
NaHCO3 solution, dried over anhydrous Na2SO4, and evaporated
in vacuo. Chromatography on a silica gel column yielded 29 (66
mg, 85%).
Reduction of Methyl 2R,23-Dihydroxy-3-oxo-olean-12-en-28-
oate (29) with NaBH4. Compound 29 (200 mg, 0.40 mmol) was
dissolved in i-PrOH/H2O (3:1) (10 mL), and NaBH4 (70 mg, 2
mmol) was added. The reaction mixture was stirred at reflux for
12 h. The excess of reagent was destroyed with NaHSO4, and the
reaction mixture was extracted with CH2Cl2. The organic layer was
dried with Na2SO4, filtered, and concentrated under reduced
pressure. The solid residue was purified on a silica gel chroma-
tography column to afford 30 (161 mg, 80%) as a colorless oil:
[R]20D +39 (c 1, CHCl3); IR (CHCl3) 3377, 2932, 1733, 1459, 1164,
756 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.26 (1H, dd, J1 ) J2 )
3.6 Hz), 4.09 (1H, d, J ) 11.1 Hz), 3.86 (1H, ddd, J1 ) 4.6 Hz,
J2 ) 9.4 Hz, J2 ) 9.8 Hz), 3.60 (3H, s), 3.35 (1H, d, J ) 11.1 Hz),
3.14 (1H, d, J ) 9.4 Hz) 2.84 (1H, dd, J1 ) 4.2 Hz, J2 ) 14.0 Hz),
1.26 (3H, s), 1.11 (3H, s), 0.92 (3H, s), 0.91 (3H, s), 0.88 (3H, s),
0.68 (3H, s); 13C NMR (75 MHz, CDCl3) δ 16.9, 17.2, 18.5, 23.0,
23.1, 23.8, 23.8, 26.0, 27.8, 30.8, 32.5, 32.9, 33.1, 34.0, 38.3, 39.4,
41.4, 41.8, 43.4, 46,0, 46.5, 46.8, 47.8, 51.8, 56.0, 68.3, 69.2, 85.5,
122.1, 144.0, 178.3; HRMS m/z calcd for C31H50O5Na 525.3556
[M + Na]+, found 525.3557.
Hydrolysis of Methyl 2R-Benzoyloxy-24-acetoxy-3-hydroxy-
iminoolean-12-en-28-oate (25). To a buffered solution of TiCl3
(0.15 mL of 20% aqueous HCl solution containing 19% TiCl3) and
NH4OAc (70 mg, 0.9 mmol) in water (3 mL) was added a solution
of oxime 25 (150 mg, 0.21 mmol) in THF (5 mL). The mixture
was stirred at rt for 4 h and extracted with CH2Cl2. The extract
was washed with saturated aqueous NaHCO3 solution, dried over
Na2SO4, filtered, and evaporated in vacuo to afford a solid that
was purified by silica gel flash chromatography column to give 28
(103 mg, 75%) as a colorless oil: [R]20 ) 30 (c 1, CHCl3); IR
D
1
(CHCl3) 2947, 1723, 1272, 1234, 756, 712 cm-1; H NMR (300
Reduction of Methyl 3-oxoMaslinate Derivatives 27, 28, and
29 with LiAlH4. Compound 27 (200 mg, 0.40 mmol) was dissolved
in dry THF (10 mL) and a 1 M solution of LiAlH4 in THF (1 mL)
was added. The reaction mixture was stirred for 1 h at reflux, the
excess of the reagent was destroyed with MeOH, and the solvent
was concentrated under reduced pressure. The crude product was
purified on a silica column to give 31 (95%) as a colorless oil:
[R]20D +43 (c 1, CHCl3); IR (CHCl3) 3366, 2926, 1459, 1048, 756
cm-1;1H NMR (300 MHz, CDCl3) δ 5.18 (1H, dd, J1 ) J2 ) 3.3
Hz), 4.10 (1H, d, J ) 11.4 Hz), 3.73 (1H, ddd, J1 ) 4.5 Hz, J2 )
9.8 Hz, J2 ) 11.4 Hz), 3.52 (1H, d, J ) 11.4 Hz), 3.36 (1H, d,
J ) 11.4 Hz), 3.19 (1H, d, J ) 11.4 Hz), 3.14 (1H, d, J ) 9.8 Hz),
1.27 (3H, s), 1.14 (3H, s), 0.94 (3H, s), 0.89 (3H, s), 0.87 (3H, s),
0.86 (3H, s); 13C NMR (75 MHz, CDCl3) δ 16.8, 17.5, 18.5, 22.0,
23.0, 23.8, 23.9, 25.6, 26.0, 31.0, 31.1, 32.8, 33.3, 34.2, 37.0, 38.2,
39.4, 41.8, 42.4, 43.4, 46,6, 46.6, 47.7, 55.9, 65.7, 69.2, 69.7, 85.5,
122.1, 144.0; HRMS m/z calcd for C30H50O4Na 497.3606 [M +
Na]+, found 497.3602. A similar procedure was followed for 28
and 29.
Demethylation at C-28 of 2R,3â,24-Trihydroxyolean-12-en-
28-oate (30). Compound 30 (200 mg, 0.39 mmol) was dissolved
in DMF (3 mL), and LiBr (10 eq) was added. The reaction mixture
was stirred at reflux for 48 h, and DMF was removed at reduced
pressure. The crude product was purified on a silica column to
afford 3213 (174 mg, 90%). IR (CHCl3) 3412, 2927, 1625, 1458,
756 cm-1;1H NMR (300 MHz, CDCl3) δ 5.24 (1H, dd, J1 ) J2 )
3.5 Hz), 4.01 (1H, d, J ) 11.1 Hz), 3.77 (1H, ddd, J1 ) 4.4 Hz,
J2 ) 9.8 Hz, J2 ) 11.5 Hz), 3.37 (1H, d, J ) 11.1 Hz), 3.04 (1H,
d, J ) 9.8 Hz), 2.84 (1H, dd, J1 ) 5.9 Hz, J2 ) 13.4 Hz), 1.22
(3H, s), 1.15 (3H, s), 0.97 (3H, s), 0.93 (3H, s), 0.90 (3H, s), 0.78
(3H, s); 13C NMR (75 MHz, CDCl3) δ 17.5, 17.6, 19.8, 23.8, 23.8,
24.1, 24.8, 26.4, 28.8, 31.6, 33.5, 33.8, 34.2, 34.9, 39.1, 40.6, 42.7,
42.9, 44.4, 47,2, 47.6, 47.8, 49.2, 57.2, 66.2, 69.6, 86.0, 123.4,
145.3, 181.8; HRMS m/z calcd for C30H48O5Na 511.3399 [M +
Na]+, found 511.3401.
MHz, CDCl3) δ 7.4-8.1 (5H, m), 5.83 (1H, dd, J1 ) 6.1 Hz, J2 )
13.2 Hz), 5.28 (1H, dd, J1 ) J2 ) 3.6 Hz), 4.79 (1H, d, J ) 11.6
Hz), 4.00 (1H, d, J ) 11.6 Hz), 3.63 (3H, s), 2.87 (1H, dd, J1 )
4.1 Hz, J2 ) 13.6 Hz), 2.41 (1H, dd, J1 ) 6.1 Hz, J2 ) 12.4 Hz),
2.04 (3H, s), 1.39 (3H, s), 1.24 (3H, s), 1.11 (3H, s), 0.92 (3H, s),
0.89 (3H, s), 0.78 (3H, s); 13C NMR (75 MHz, CDCl3) δ 16.9,
17.0, 19.8, 20.1, 20.8, 23.1, 23.7, 23.9, 26.0, 27.8, 30.8, 32.4, 32.8,
33.2, 33.9, 38.1, 39.5, 41.3, 41.8, 45.9, 46.3, 46.7, 47.8, 51.7, 53.3,
58.4, 66.2, 72.7, 121.6, 128.4, 128.4, 129.9, 129.9, 130.3, 133.1,
144.2, 165.5, 171.1, 178.2, 206.1; HRMS m/z calcd for C40H54O7-
Na 669.3768 [M + Na]+, found 669.3767.
Hydrolysis of Methyl 2R,24-Dihydroxy-3-hydroxyiminoolean-
12-en-28-oate (26). To a buffered solution of TiCl3 (0.5 mL of
20% aqueous HCl solution containing 19% TiCl3) and NH4OAc
(200 mg, 2.6 mmol) in water (8 mL) was added a solution of oxime
26 (400 mg, 0.78 mmol) in THF (15 mL). The mixture was stirred
at rt for 4 h and extracted with CH2Cl2. The extract was washed
with saturated aqueous NaHCO3 solution, dried over Na2SO4,
filtered, and evaporated in vacuo to afford a solid that was purified
by silica gel flash chromatography column to give 29 (330 mg,
85%) as a colorless oil: [R]D +64 (c 1, CHCl3); IR (CHCl3) 3467,
2947, 1720, 1461, 1164, 756 cm-1; 1H NMR (300 MHz, CDCl3) δ
5.26 (1H, dd, J1 ) J2 ) 3.6 Hz), 4.54 (1H, dd, J1 ) 6.4 Hz, J2 )
12.1 Hz), 4.12 (1H, d, J ) 11.1 Hz), 3.60 (3H, s), 3.55 (1H, d,
J ) 11.1 Hz), 2.84 (1H, dd, J1 ) 4.0 Hz, J2 ) 13.8 Hz), 2.38 (1H,
dd, J1 ) 6.5 Hz, J2 ) 12.5 Hz), 2.24 (1H, dd, J1 ) J2 ) 6.5 Hz),
1.25 (3H, s), 1.24 (3H, s), 1.07 (3H, s), 0.90 (3H, s), 0.87 (3H, s),
0.72 (3H, s); 13C NMR (75 MHz, CDCl3): δ 16.8, 17.0, 19.3, 19.8,
23.0, 23.7, 23.8, 26.0, 27.7, 30.8, 32.4, 32.9, 33.1, 33.9, 37.7, 39.4,
41.3, 41.7, 45.9, 46.7, 47.6, 49.6, 51.8, 54.7, 58.6, 65.7, 70.0, 121.8,
144.0, 178.3, 214.8; HRMS m/z calcd for C31H48O5Na 523.3407
[M + Na]+, found 523.3399.
Saponification of Methyl 2R,24-Diacetoxy-3-oxoolean-12-en-
28-oate (27). Diacetoxy ketone 27 (100 mg, 0.47 mmol) was
dissolved in MeOH (2 mL), and MeOH/H2O (70%) (2 mL)
containing KOH (20%) was added. The reaction mixture was stirred
at rt for 2 h, neutralized with (20%) HCl solution, and extracted
with CH2Cl2. The extract was washed with saturated NaHCO3
solution, dried over anhydrous Na2SO4, and evaporated in vacuo.
Chromatography on a silica gel column yielded 29 (77 mg, 90%).
Saponification of Methyl 2R-Benzoyloxy-24-acetoxy-3-oxoolean-
12-en-28-oate (28). Benzoyloxyacetoxy ketone 28 (100 mg, 0.15
mmol) was dissolved in MeOH (2 mL), and MeOH/H2O (70%) (2
mL) containing KOH (20%) was added. The reaction mixture was
stirred at rt for 2 h, neutralized with (20%) HCl solution, and
extracted with CH2Cl2. The extract was washed with saturated
Acknowledgment. This work was supported by a grant from
the Comisio´n Interministerial de Ciencia y Tecnolog´ıa and by
a project from the Ministerio de Educacio´n y Cultura. We thank
David Nesbitt for language help.
Supporting Information Available: Copies of 1H and 13C
spectra of all new compounds, theoretical structures and cartesian
coordinates for compounds 6 and 21. This material is avalaible free
of charge via the Internet at http://pubs.acs.org.
JO070116E
J. Org. Chem, Vol. 72, No. 9, 2007 3509